1. Aza Diels-Alder Reaction of N-Arylimines with Pyruvate Derivatives:
A Route to 2-Phenyl-Quinoline-4-Carboxylates and 2-Phenyl-Quinoline-4-Carboxamides
 Dorothée Duvelleroy, Cécile Perrio, Marie-Claire Lasne
Laboratoire de Chimie Moléculaire et Thio-organique, UMR CNRS 6507, ENSICAEN and
University of Caen-Basse-Normandie, 6 Boulevard du Maréchal Juin, CAEN cedex
E.mail:
Research for a rapid synthesis of 2-phenylquinoline 4-carboxylic derivatives:
starting from easily available precursors
adaptable for the development of radioligands of NK-3 receptors, analogues of the selective antagonist Talnetant for medical imaging using positron emission tomography.
Bennacef, I.; Tymciu, S.; Dhilly, M.; Mongin, F.; Queguiner, G.; Lasne, M.-C.; Barré, L.; Perrio, C. J. Org. Chem (7),
AIM
BACKGROUND
Giardina, G. A. M. ; Sarau, H. M. ; Farina, C. ; A. D. ; Grugni, M. ; Raveglia, L. F. ; Schmidt, D. B.; Rigolio, R.; Luttmann, M.; Vecchietti, V.; Hay, D. W. P., J. Med. Chem., 1997, 40,
Pfitzinger
Doebner
Aboul-Enein, H. A.; Ibrahim, S. A. J. Fluorine Chem. 1992, 59,
Pfitzinger and Doebner reactions are the two main approaches currently used for the construction of a 4-substituted quinolinic structure. However, both of them present several limitations such as long reaction times, low yields, lack of reproductibility, or need for strong basic conditions incompatible with sensitive substituents.
Recently, the aza-Diels-Alder reaction of N-arylimines with 2-methoxypropene was successfully applied by Makioka et coll. to the synthesis of quinolines. However, only 4-methyl-2-phenylquinoline was synthesized.
Makioka
Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara, Y. Synthesis 1995, 801.
RESULTS
Optimization of the conditions
We anticipated that the reaction of N-arylimines 2 with enol ether 3, derived from pyruvic esters or
pyruvic amides could yield quinoline-4-carboxylic derivatives 1.
Lewis Acid
( 50 mol %)
Solvent
Times
Activation
(barb, W, °C)
Yield %
Yb(OTf)3a
CH3CN
3 min
150 W e
InI3 36
InBr3 30
InCl3 57
24h
Reflux, 90°C 41
CH3CN/ CH2Cl2
High Pressure
(16 Kbar, 60°C) 10
Influence of the nature of Y and Z in 3
a- 40 mol %. b- apparatus:PSIKA
Acrylic compound Y Z
InCl3 (eq.)
Yield % (isolated) 3a
OEt
OMe 1 24
0.5 57 3b
OTf 20 3c Br
4 (polymerization of 3c) 3d
NHiPr 36
Other results: Solvent (yield %): EtOH (18), Toluene (0), DMF (0), CH2Cl2/CH3CN (1/1) (25), H2O/CH3CN (1/1) (0), THF/CH3CN (1/1) (11), Perfluoro(methylcyclohexane) (39), [bbim]Br (0), [bbim]BF4 (0).
Synthesis of 2-phenylquinoline-4-carboxylates and carboxamides
Synthesis of acrylic derivatives 3 Y R1 R2 R3
Yield % (isolated)
OEt H 57 F 40
NHiPr
6-F 25
(S)-NHCHPh Et 47 35 49
8-F 53 48
Tranchant, M.J.; Dalla, V.; Jabin, I.; Decroix, B.; Tetrahedron 2002, 58,
Rachon, J.; Goedken, V.; Walkorsky, H.M.; J.Org.Chem. 1989, 54,
CONCLUSION
A rapid synthesis of 2-phenylquinoline-4-carboxylates and carboxamides has been developed, according to an aza Diels-Alder reaction of N-arylimines with electron enriched acrylic acid derivatives :
- microwave activation (3 min, 150 W)
indium (III) chloride catalysis (0.5 eq for Y= OEt and 1 eq. for Y= NHR1)
yields up to 57 % with ethyl-2-methoxyacrylate or with 2-methoxyacrylamide.